Lenvatinib and Cu2-XS nanocrystals co-encapsulated in poly(D,L-lactide-co-glycolide) for synergistic chemo-photothermal therapy against advanced hepatocellular carcinoma

Lenvatinib (LT) is gradually replacing sorafenib as an alternative targeted drug for advanced hepatocellular carcinoma (HCC). However, the anticancer effect of LT is still limited by low cytotoxicity, multidrug resistance (MDR), and tumor relapse. Herein, we constructed a smart biophotonic nanoplatform to overcome the barriers with high-performance. LT and copper sulfide nanocrystals (Cu2-xS NCs) with excellent near-infrared-II (NIR-II) zone photothermal properties were co-encapsulated in poly (D,L-lactide-co-glycolide) (PLGA) through nanoprecipitation. Both in vitro and in vivo evaluations demonstrated that Cu2-xS NCs enhanced the anticancer efficacy of LT without recurrence. In addition, the presence of copper ions could consume glutathione (GHS) and produce oxygen, likely suppressing the expression of P-glycoprotein (P-gp) and reversing the MDR property of LT. More importantly, the synergistic chemo-photothermal therapy with LT and Cu2-xS NCs was more effective than any single therapy or their theoretical combination. This nanoplatform is promising for future LT-based treatment strategy for HCC therapy.